Spontaneous degradation via diketopiperazine formation of peptides containing a tetrahydroisoquinoline‐3‐carboxylic acid residue in the 2‐position of the peptide sequence

The δ‐opioid antagonists H‐Tyr‐Tic‐Phe‐OH (Tic = tetrahydroisoquinoline‐3‐carboxylic acid) and H‐Tyr‐Tic‐Phe‐Phe‐NH2 were shown to undergo spontaneous Tyr‐Tic diketopiperazine formation with concomitant cleavage of the Tic‐Phe peptide bond in DMSO but not in aqueous solution at pH 7.7.